Preeclampsia (PE) is an important cause of maternal and perinatal mortality and morbidity. The risk of adverse outcome is much higher when the disease is severe and of early onset requiring delivery before 37 weeks' gestation (preterm PE) than at term. A major challenge in modern obstetrics is early identification of pregnancies at high-risk of preterm PE and undertaking of the necessary measures to improve placentation and reduce the prevalence of the disease.

Aspirin from 23 weeks

Yu CK, Papageorghiou AT, Parra M, Palma Dias R, Nicolaides KH; Fetal Medicine Foundation second trimester screening group. Randomized controlled trial using low-dose aspirin in the prevention of pre-eclampsia in women with abnormal uterine artery Doppler at 23 weeks’ gestation. Ultrasound Obstet Gynecol 2003;22:233-9.

In this study we tested the hypothesis that in women identified as being at high-risk for pre-eclampsia, because of impaired flow in the uterine arteries, the prophylactic use of low-dose aspirin from 23 weeks of gestation can reduce the incidence of PE. We used color and pulsed Doppler to measure the flow in the uterine arteries in 19,950 singleton pregnancies at 22-24 weeks of gestation. Those women exhibiting increased impedance were recruited into a randomized study of aspirin 150 mg per day or placebo. We compared the two groups for the incidence of PE and the other consequences of impaired placentation.

The screening study identified 844 women (4.2%) as being at high risk of uteroplacental insufficiency. After exclusion and refusal, 560 women were randomly allocated to aspirin 150 mg or placebo per day until 36 weeks' gestation. There were no significant differences between the aspirin and placebo groups in either the incidence of PE (18% vs. 19%, P = 0.6) or PE requiring delivery below 34 weeks (6% vs. 8%, P = 0.36). Furthermore, the administration of aspirin did not significantly alter the incidence of preterm delivery (24% vs. 27%, P = 0.46), birth weight below the 5th centile (22% vs. 24%, P = 0.4), perinatal death (3% vs. 1%, P = 0.33) or placental abruption (4% vs. 2%, P = 0.12).

It was concluded that in pregnancies with impaired placentation, as demonstrated by increased impedance to flow in the uterine arteries, the daily administration of 150 mg aspirin after 23 weeks of gestation does not prevent the subsequent development of PE.

ASPRE trial: Aspirin from 12 weeks

Rolnik DL, Wright D, Poon LC, O'Gorman N, Syngelaki A, de Paco Matallana C, Akolekar R, Cicero S, Janga D, Singh M, Molina FS, Persico N, Jani JC, Plasencia W, Papaioannou G, Tenenbaum-Gavish K, Meiri H, Gizurarson S, Maclagan K, Nicolaides KH. Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. N Engl J Med 2017;377:613-622.

The objectives of this study were to examine if the prophylactic use of low-dose aspirin from the first-trimester of pregnancy in women at increased risk for preterm PE can reduce the incidence of the disease. In the ASPRE trial (Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention) women with singleton pregnancies had screening by means of an algorithm that combines maternal factors, mean arterial pressure (MAP), uterine-artery pulsatility index (UTPI), and maternal serum placental growth factor (PLGF) and pregnancy-associated plasma protein A (PAPP-A) at 11-13 weeks’ gestation. Screening was carried out in 26,941 pregnancies. Those with an estimated risk for preterm PE of >1 in 100 were invited to participate in a double-blind trial of aspirin (150 mg/day) vs. placebo from 11 to 14 until 36 weeks’ gestation.

Preterm PE, which was the primary outcome, occurred in 1.6% (13/798) participants in the aspirin group, as compared with 4.3% (35/822) in the placebo group (odds ratio in the aspirin group with adjustment for the effect of the estimated risk for preterm-PE at screening and participating center 0.38; 95% confidence interval, 0.20 to 0.74). The incidence of PE at <34 weeks was reduced by 82%. The trial showed that aspirin had no significant effect in reducing the risk of term PE. Adherence was good, with a reported intake of 85% or more of the required number of tablets in 79.9% of the participants. There were no significant between-group differences in the incidence of neonatal adverse outcomes or other adverse events.

It was concluded that treatment with low-dose aspirin in women at high risk for preterm PE reduces substantially the incidence of this disease.

STATIN trial: Statin from 35 weeks

Döbert M, Varouxaki AN, Mu AC, Syngelaki A, Ciobanu A, Akolekar R, De Paco Matallana C, Cicero S, Greco E, Singh M, Janga D, Del Mar Gil M, Jani JC, Bartha JL, Maclagan K, Wright D, Nicolaides KH. Pravastatin Versus Placebo in Pregnancies at High Risk of Term Preeclampsia. Circulation 2021;144:670-679.

The objective of the trial was to examine if prophylactic use of pravastatin from 35-37 weeks of gestation in women at increased risk for preeclampsia can reduce the incidence and severity of the disease. Effective screening for term preeclampsia is provided by a combination of maternal factors with measurements of mean arterial pressure, serum placental growth factor, and serum soluble fms-like tyrosine kinase-1 at 35 to 37 weeks of gestation, with a detection rate of ≈75% at a screen-positive rate of 10%. Screening was carried out in 29,816 singleton pregnancies. Those with an estimated risk for preeclampsia of >1 in 20 were invited to participate in a double-blind trial of pravastatin (20 mg/day) vs. placebo from 35 to 37 until delivery or 41 weeks.

Preeclampsia which was the primary outcome of the trial, occurred in 14.6% (80 of 548) of participants in the pravastatin group and in 13.6% (74 of 543) in the placebo group. Allowing for the effect of risk at the time of screening and participating center, the mixed-effects Cox regression showed no evidence of an effect of pravastatin (hazard ratio for statin/placebo, 1.08 [95% CI, 0.78-1.49]; P=0.65). There was no evidence of interaction between the effect of pravastatin, estimated risk of preeclampsia, pregnancy history, adherence, and aspirin treatment. There was no significant between-group difference in the incidence of any secondary outcomes, including gestational hypertension, stillbirth, abruption, delivery of small for gestational age neonates, neonatal death, or neonatal morbidity. There was no significant between-group difference in the treatment effects on serum placental growth factor and soluble fms-like tyrosine kinase-1 concentrations 1 and 3 weeks after randomization. Adherence was good, with reported intake of ≥80% of the required number of tablets in 89% of participants. There were no significant between-group differences in neonatal adverse outcomes or other adverse events.

It was concluded pravastatin in women at high risk of term preeclampsia did not reduce the incidence of delivery with preeclampsia.